Gene Number: 114548

Location: 1q44

Key Functions: Inflammasome activation, innate immune surveillance, pro-inflammatory cytokine maturation, regulation of pyroptosis

The NLRP3 gene, located on chromosome 1q44, encodes the NLR family pyrin domain-containing protein 3, a cytosolic pattern-recognition receptor that plays a central role in the innate immune system’s ability to detect cellular stress and pathogenic threats. Functionally, NLRP3 acts as a molecular sentinel that monitors disruptions in cellular homeostasis—ranging from ion fluxes and mitochondrial dysfunction to reactive oxygen species (ROS) accumulation and lysosomal damage.

When activated, NLRP3 oligomerizes through its central NACHT domain and recruits the adaptor protein ASC via pyrin–pyrin domain interactions. ASC then binds pro–caspase-1, forming the NLRP3 inflammasome—a supramolecular complex that enables the autocatalytic activation of caspase-1. This cascade converts pro–IL-1β and pro–IL-18 into their mature cytokine forms, which subsequently drive local and systemic inflammation.

Concurrently, caspase-1 cleaves gasdermin D (GSDMD), forming membrane pores that initiate pyroptosis, a lytic and pro-inflammatory mode of programmed cell death that facilitates cytokine release and immune recruitment.

At the genetic level, NLRP3 serves as a key determinant of inflammatory sensitivity. Gain-of-function mutations, particularly within the NACHT domain, result in constitutive inflammasome activation and underpin a group of rare monogenic disorders known as Cryopyrin-Associated Periodic Syndromes (CAPS), including Muckle–Wells Syndrome and Neonatal-Onset Multisystem Inflammatory Disease. These mutations drive unrestrained IL-1β secretion and systemic inflammation. Beyond monogenic syndromes, common single nucleotide polymorphisms (SNPs) such as rs35829419 (Q705K) and rs10754558 have been associated with multifactorial conditions including type 2 diabetes, Alzheimer’s disease, Crohn’s disease, and atherosclerosis, largely through altered inflammasome activation thresholds and dysregulated cytokine expression.

In a broader physiological sense, NLRP3 operates at the intersection of metabolic and immune regulation, translating metabolic disturbances—such as mitochondrial dysfunction, excessive lipid accumulation, and oxidative stress—into inflammatory signals. This makes it a molecular bridge between innate immunity, metabolism, and chronic disease pathology. Properly regulated, NLRP3-mediated signaling is vital for host defense and tissue repair; when dysregulated, it becomes a potent driver of chronic low-grade inflammation and immunometabolic imbalance.